US7485625B2ExpiredUtilityA1
Inhibitors of hepatitis C virus NS3/NS4a serine protease
Est. expiryDec 11, 2023(expired)· nominal 20-yr term from priority
A61P 43/00A61P 31/12A61P 31/20A61P 1/16C07D 401/12C07D 403/12C07K 5/0202C07D 209/52C07D 417/12C07K 7/02C07D 409/12
88
PatentIndex Score
33
Cited by
9
References
35
Claims
Abstract
The present invention discloses novel compounds which have HCV protease inhibitory activity as well as methods for preparing such compounds. In another embodiment, the invention discloses pharmaceutical compositions comprising such compounds as well as methods of using them to treat disorders associated with the HCV protease.
Claims
exact text as granted — not AI-modified1. A compound, or enantiomers, stereoisomers, rotamers, tautomers, diastereomers, or racemates of said compound, or a pharmaceutically acceptable salt, solvate or ester of said compound, said compound having the general structure shown in Formula I:
wherein:
R 1 is H, OR 8 , NR 9 R 10 , or CHR 9 R 10 , wherein R 8 , R 9 and R 10 can be the same or different, each being independently selected from the group consisting of H, alkyl-, aryl-, heteroalkyl-, heteroaryl-, cycloalkyl-, cycloalkyl-, arylalkyl-, and heteroarylalkyl;
E and J can be the same or different, each being independently selected from the group consisting of R, OR, NHR, NRR 7 , SR, halo, and S(O 2 )R, or E and J can be directly connected to each other to form either a three to eight-membered cycloalkyl, or a three to eight-membered heterocyclyl moiety;
Z is N(H), N(R), or O;
G is C(═O) or S(O 2 ), with the proviso that when Z is O, G is not S(O 2 );
Y is selected from the group consisting of:
R, R 7 , R 2 , R 3 , R 4 and R 5 can be the same or different, each being independently selected from the group consisting of H, alkyl-, alkenyl-, alkynyl-, cycloalkyl-, heteroalkyl-, heterocyclyl-, aryl-, heteroaryl-, (cycloalkyl)alkyl-, (heterocyclyl)alkyl-, aryl-alkyl-, and heteroaryl-alkyl-, wherein each of said heteroalkyl, heteroaryl and heterocyclyl independently has one to six oxygen, nitrogen, sulfur, or phosphorus atoms;
wherein each of said alkyl, heteroalkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and heterocyclyl moieties can be unsubstituted or optionally independently substituted with one or more moieties selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, heterocyclyl, halo, hydroxy, thio, alkoxy, aryloxy, alkylthio, arylthio, amino, amido, ester, carboxylic acid, carbamate, urea, ketone, aldehyde, cyano, nitro, sulfonamido, sulfoxide, sulfone, sulfonyl urea, hydrazide, and hydroxamate.
2. The compound of claim 1 , wherein R 2 is selected from the group consisting of the following moieties:
3. The compound of claim 1 , wherein R 3 is selected from the group consisting of:
wherein R 31 is OH or O-alkyl; and
R 32 is H, C(O)CH 3 , C(O)OtBu or C(O)N(H)tBu.
4. The compound of claim 3 , wherein R 3 is selected from the group consisting of:
5. The compound of claim 1 , wherein
is selected from the group consisting of:
wherein
Y 31 is selected from the group consisting of: OR, NHR and NRR 7 and
Y 32 is selected from the group consisting of:
6. The compound of claim 1 , wherein Z is NH.
7. The compound of claim 1 , wherein Z is N(R).
8. The compound of claim 1 , wherein Z is OG is C(═O).
9. The compound of claim 1 , wherein G is present and is C(═O) or S(O 2 ).
10. The compound of claim 1 , wherein Y is selected from the group consisting of:
11. The compound of claim 1 , wherein:
is selected from the group consisting of:
12. A pharmaceutical composition comprising as an active ingredient at least one compound of claim 1 .
13. The pharmaceutical composition of claim 12 for use in treating disorders associated with HCV.
14. The pharmaceutical composition of claim 12 additionally comprising at least one pharmaceutically acceptable carrier.
15. The pharmaceutical composition of claim 14 , additionally containing at least one antiviral agent.
16. The pharmaceutical composition of claim 15 , still additionally containing at least one interferon.
17. The pharmaceutical composition of claim 16 , wherein said at least one antiviral agent is ribavirin and said at least one interferon is α-interferon or pegylated interferon.
18. A method of treating disorders associated with the HCV, said method comprising administering to a patient in need of such treatment a pharmaceutical composition which comprises therapeutically effective amounts of at least one compound of claim 1 .
19. The method of claim 18 , wherein said administration is oral or subcutaneous.
20. A method of preparing a pharmaceutical composition for treating the disorders associated with the HCV, said method comprising bringing into intimate contact at least one compound of claim 1 and at least one pharmaceutically acceptable carrier.
21. A compound exhibiting HCV protease inhibitory activity, or enantiomers, stereoisomers, rotamers, tautomers, diastereomers, or racemates of said compound, or a pharmaceutically acceptable salt, solvate or ester of said compound, said compound being selected from the compounds of structures listed below:
22. A compound, or enantiomers, stereoisomers, rotamers, tautomers, diastereomers, or racemates of said compound, or a pharmaceutically acceptable salt, solvate or ester of said compound, said compound being selected from the compounds of structures listed below:
23. A pharmaceutical composition for treating disorders associated with the HCV, said composition comprising therapeutically effective amount of one or more compounds in claim 22 and a pharmaceutically acceptable carrier.
24. The pharmaceutical composition of claim 23 , additionally containing at least one antiviral agent.
25. The pharmaceutical composition of claim 24 , still additionally containing at least one interferon or PEG-interferon alpha conjugate.
26. The pharmaceutical composition of claim 25 , wherein said at least one antiviral agent is ribavirin and said at least one interferon is α-interferon or pegylated interferon.
27. A method of treatment of a hepatitis C virus associated disorder, comprising administering an effective amount of one or more compounds of claim 22 .
28. A method of modulating the activity of hepatitis C virus (HCV) protease, comprising contacting HCV protease with one or more compounds of claim 22 .
29. A method of treating or ameliorating one or more symptoms of hepatitis C (HCV), comprising administering a therapeutically effective amount of one or more compounds of claim 22 .
30. The method of claim 29 , wherein the HCV protease is the NS3/NS4a protease.
31. The method of claim 29 , wherein the compound or compounds inhibit HCV NS3/NS4a protease.
32. A method of modulating the processing of hepatitis C virus (HCV) polypeptide, comprising contacting a composition containing the HCV polypeptide under conditions in which said polypeptide is processed with one or more compounds of claim 22 .
33. A compound of claim 1 in purified form.
34. A compound, or enantiomers, stereoisomers, rotamers, tautomers, diastereomers, or racemates of said compound, or a pharmaceutically acceptable salt, solvate or ester of said compound, said compound having the general structure shown in Formula I:
wherein:
R 1 is NR 9 R 10 , and R 9 is H, R 10 is H or R 14 , wherein R 14 is alkyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, alkyl-aryl-, alkyl-heteroaryl-, aryl-alkyl-, alkenyl, alkynyl or heteroaryl-alkyl-;
E and J can be the same or different, each being independently selected from the group consisting of R, OR, NHR, NRR 7 , SR halo, and S(O 2 )R, or E and J can be directly connected to each other to form either a three to eight-membered cycloalkyl, or a three to eight-membered heterocyclyl moiety;
Z is N(H), N(R), or O, G is C(═O) or S(O 2 ) with the proviso that when Z is O, G is not S(O 2 ) and;
Y is selected from the group consisting of
R, R 7 , R 2 , R 3 , R 4 and R 5 can be the same or different, each being independently selected from the group consisting of H, alkyl-, alkenyl-, alkynyl-, cycloalkyl-, heteroalkyl-, heterocyclyl-, aryl-, heteroaryl-, (cyclcoalkyl)alkyl-, (heterocyclyl)alkyl-, aryl-alkyl-, and heteroaryl-alkyl-, wherein each of said heteroalkyl, heteroaryl and heterocyclyl independently has one to six oxygen, nitrogen, sulfur, or phosphorus atoms;
wherein each of said alkyl, heteroalkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and heterocyclyl moieties can be unsubstituted or optionally independently substituted with one or more moieties selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, heterocyclyl, halo, hydroxy, thio, alkoxy, aryloxy, alkylthio, arylthio, amino, amido, ester, carboxylic acid, carbamate, urea, ketone, aldehyde, cyano, nitro, sulfonamido, sulfoxide, sulfone, sulfonyl urea, hydrazide, and hydroxamate.
35. The compound of claim 34 , wherein R 14 is selected from the group consisting of:Cited by (0)
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